Multiple myeloma (MM) is a devastating hematologic malignancy that affects over 20,000 new patients every year in the USA. It typically responds well to treatment with DNA alkylators, glucocorticoids, proteasome inhibitors, and the IMiD class of Immunomodulator (thalidomide, lenalidomide and pomalidomide). Unfortunately, over time the disease becomes resistant to these drugs and patients relapse and die. We have identified 4 key areas of research that promise to translate into rapid clinical gains for the treatment of patients. 1) Develop dramatically new strategies to treat MM using next-generation approaches such as oncolytic virotherapy; 2) Given the success of IMiDs, study novel classes of immunomodulators with anti-MM activity, starting with SMAC mimetic compounds; 3) Determine the clinical significance of the most frequent mutation in MM, structural rearrangements of the MYC locus, and the effects of targeting MYC in patients with MM; 4) Explore clonal evolution in MM, including its contribution to drug resistance. To tackle these issues we have assembled a dedicated team of basic science and clinical investigators from all three Mayo Clinic sites, representing the largest MM program in the world. The projects are augmented by the strong collaborations of the project co-leaders, and through the three shared resource cores: Biospecimens Core, Biostatistics and Bioinformatics Core, and Administrative Core. The cores provide economy of effort and cost and support each of the projects. Finally to further enhance MM research and specifically the Aims of the 4 projects, this SPORE application supports novel translational studies through a Developmental Research Program (e.g., individual peptide monitoring by mass spectrometry to follow minimal residual disease), and through a mentored Career Development Program (e.g., developing novel immune therapies for MM) for young faculty. The historical and institutional commitment to MM research at Mayo Clinic is unequalled, and together with the leading role nationally and internationally in MM research of members of this SPORE we will be able to quickly translate our discoveries into new treatment strategies for patients with MM aimed not just at control, but ultimately to make cure become a reality.